The phenothiazine, trifluoperazine, is selectively lethal to ABCB1-expressing multidrug resistant cells
Biochem Biophys Res Commun. 2021 Jul 16;570:148-153. doi: 10.1016/j.bbrc.2021.07.031. Online ahead of print.
P-glycoprotein, member of the B-subfamily of the ATP-binding cassette (ABC) superfamily (e.g., ABCB1), has been demonstrated to confer resistance to clinically relevant anticancer drugs. Paradoxically, ABCB1-expressing multidrug resistant (MDR) cells are hypersensitivity or collateral sensitivity to non-toxic drugs. In this report, we demonstrate the capacity of trifluoperazine (TFP), a calmodulin inhibitor, to confer a collateral sensitivity onto ABCB1-overexpressing MDR cells. We show TFP-induced collateral sensitivity to be linked to ABCB1 expression and ATPase activity, as such phenotype is abolished in ABCB1-knockout MDR cells (CHORC5ΔABCB1 clones A1-A3) or with inhibitors of ABCB1 ATPase. TFP-induced collateral sensitivity is mediated by apoptotic cell death, due to enhanced oxidative stress. The findings in this study show for first time the use TFP as a collateral sensitivity drug, at clinically relevant concentrations. Moreover, given the use of trifluoperazine in the treatment for symptoms of schizophrenia and the role of ABCB1 transporter in tissue blood barriers and other physiologic functions, the finding in this study may have implications beyond cancer chemotherapy.
Comparison of hospitalized patients with COVID-19 who did and did not live in residential care facilities in Montréal: a retrospective case series
CMAJ Open. 2021 Jul 13;9(3):E718-E727. doi: 10.9778/cmajo.20200244. Print 2021 Jul-Sep.
BACKGROUND: As in other jurisdictions, the demographics of people infected with SARS-CoV-2 changed in Quebec over the course of the first COVID-19 pandemic wave, and affected those living in residential care facilities (RCFs) disproportionately. We evaluated the association between clinical characteristics and outcomes of hospitalized patients with COVID-19, comparing those did or did not live in RCFs.
METHODS: We conducted a retrospective case series of all consecutive adults (≥ 18 yr) admitted to the Jewish General Hospital in Montréal with laboratory-confirmed SARS-CoV-2 infection from Mar. 4 to June 30, 2020, with in-hospital follow-up until Aug. 6, 2020. We collected patient demographics, comorbidities and outcomes (i.e., admission to the intensive care unit, mechanical ventilation and death) from medical and laboratory records and compared patients who did or did not live in public and private RCFs. We evaluated factors associated with the risk of in-hospital death with a Cox proportional hazard model.
RESULTS: In total, 656 patients were hospitalized between March and June 2020, including 303 patients who lived in RCFs and 353 patients who did not. The mean age was 72.9 (standard deviation 18.3) years (range 21 to 106 yr); 349 (53.2%) were female and 118 (18.0%) were admitted to the intensive care unit. The overall mortality rate was 23.8% (156/656), but was higher among patients living in RCFs (36.6% [111/303]) compared with those not living in RCFs (12.7% [45/353]). Increased risk of death was associated with age 80 years and older (hazard ratio [HR] 2.39, 95% confidence interval [CI] 1.35-4.24), male sex (HR 1.74, 95% CI 1.25-2.41), the presence of 4 or more comorbidities (HR 2.01, 95% CI 1.18-3.42) and living in an RCF (HR 1.62, 95% CI 1.09-2.39).
INTERPRETATION: During the first wave of the COVID-19 epidemic in Montréal, more than one-third of RCF residents hospitalized with SARS-CoV-2 infection died during hospitalization. Policies and practices that prevent future outbreaks of SARS-CoV-2 infection in this setting must be implemented to prevent high mortality in this vulnerable population.
Epidemiology associated with the exposure to Toxoplasma gondii in Nunavik's Inuit population using the 2017 Qanuilirpitaa cross-sectional health survey
Zoonoses Public Health. 2021 Jul 12. doi: 10.1111/zph.12870. Online ahead of print.
Foci of high seroprevalence against Toxoplasma gondii are observed in Nunavik, the Inuit land of Northern Quebec (Canada). Considering the rare occurrence of felids in the region, exposure is suspected to be driven by water- and food-borne transmission routes. Hypotheses were that drinking untreated water from natural sources and eating country food mostly raw increased the risk of exposure to the parasite. Data from 1,300 Inuit participants of the 2017 Nunavik Health Survey were included in three weighted robust Poisson regression models. The effect of three types of exposure variables: (1) water treatment (yes/no) and if country food was mostly eaten raw (yes/no); (2) main source of drinking water (bottled/municipal/natural) and frequency of country food consumption (continuous) and (3) drinking water risk (low/intermediate/high) and frequency of a raw country food consumption (continuous), on the presence of Toxoplasma antibodies were estimated. Models were adjusted for age, sex and ecological region, with multiple sensitivity analyses being performed. Toxoplasma gondii seroprevalences were consistently correlated with age quadratically, sex (prevalence ratio = PRwoman/man ranged from 1.18 to 1.22), ecological region (PRHudsonBay/HudsonStrait ranged from 2.18 to 2.41; PRHudsonBay/UngavaBay ranged from 1.52 to 1.59) and consuming bivalve mollusc/urchin (PR varied from 1.02 to 1.21) across all three models. Each increase of two consumptions per month of beluga (PR ranged from 1.01 to 1.03), seal liver (PR ranged from 1.01 to 1.02) and goose (PR ranged from 1.01 to 1.02) were also associated with seropositivity, albeit more clearly in models 2 and 3, while drinking water mainly from natural (PR of 1.47) or municipal (PR = 1.42) sources compared to bottled water, was correlated with seroprevalence, although results were compatible with the null. Our results suggest that both the oocyst- (mollusc/urchin, drinking water) and cyst-borne (walrus, seal liver and goose) transmission pathways could be present in Nunavik.
Prolonged empirical antibiotic therapy is correlated with bloodstream infections and increased mortality in a tertiary care hospital in Ethiopia: bacteriology testing matters
JAC Antimicrob Resist. 2020 Jul 7;2(3):dlaa039. doi: 10.1093/jacamr/dlaa039. eCollection 2020 Sep.
BACKGROUND: Hospital-associated infection (HAI) and antimicrobial resistance (AMR) are major health threats in low- and middle-income countries (LMICs). Because diagnostic capacity is lacking throughout most of Africa, patients are commonly managed with prolonged empirical antibiotic therapy. Our goal was to assess mortality in relation to HAI and empirical therapy in Ethiopia's largest referral hospital.
METHODS: Cohort study of patients with suspected HAI at Tikur Anbessa Specialized Hospital from October 2016 to October 2018. Blood culture testing was performed on an automated platform. Primary outcomes were proportion of patients with bloodstream infection (BSI), antibiotic resistance patterns and 14 day mortality. We also assessed days of therapy (DOT) pre- and post-blood culture testing.
RESULTS: Of 978 enrolled patients, 777 had blood culture testing; 237 (30%) had a BSI. Enterobacteriaceae were isolated in 49%; 81% of these were cephalosporin resistant and 23% were also carbapenem resistant. Mortality at 14 days was 31% and 21% in those with and without BSI, respectively. Ceftriaxone resistance was strongly correlated with mortality. Patients with BSI had longer DOT pre-blood culture testing compared with those without BSI (median DOT 12 versus 3 days, respectively, P < 0.0001). After testing, DOT were comparable between the two groups (20 versus 18 days, respectively).
CONCLUSIONS: BSI are frequent and fatal among patients with suspected HAI in Ethiopia. Highly resistant blood isolates are alarmingly common. This study provides evidence that investing in systematic blood culture testing in LMICs identifies patients at highest risk of death and that empirical management is frequently inappropriate. Major investments in laboratory development are critical to achieve better outcomes.